5-(2-imidazolinylamino)-benzimidazole derivatives, their preparation and their use as .alpha.-adrenoceptor agonists with improved metabolic stability

ABSTRACT

Benzimidazole compounds having the generic structure:                    
     are used to treat alpha-2 mediated disorders, including nasal congestion, glaucoma, asthma, migraine, and diarrhea.

This application is a 371 of PCT/US98/24694 filed Nov. 20, 1998 whichclaims the benefit of U.S. Provisional Applications 60/066,767 filedNov. 24, 1997 and 60/066,780 filed Nov. 25, 1997.

TECHNICAL FIELD

The subject invention is directed to certain substituted benzimidazolecompounds that have improved resistance to metabolism in primates. Thesubject compounds are alpha adrenoceptor agonists and are useful intreating alpha agonist associated disorders.

BACKGROUND OF THE INVENTION

Alpha adrenergic receptors, agonists, antagonists, and compounds relatedin structure to those of this invention are disclosed in the followingreferences: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C.Thoolen, “12.1α-Adrenergic Receptors”, Comprehensive MedicinalChemistry, Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor,eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. &P. A. van Zwieten, “α-Adrenoceptor Agonists and Antagonists”, Drugs ofthe Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H.P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, “FurtherValidation of in vivo and in vitro Pharmacological Procedures forAssessing the α₁ and α₂-Selectivity of Test Compounds: (2)α-Adrenoceptor Agonists”, European Journal of Pharmacology, Vol. 129(1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C.Thoolen, B. Wilffert, H. Batink & P. A. van Zwieten, “QuantitativeRelationships between α-Adrenergic Activity and Binding Affinity ofα-Adrenoceptor Agonists and Antagonists”, Journal of MedicinalChemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge,P. B. M. W. M. Timmermans & P. A. van Zwieten, “Selectivity of SomeAlpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2Adrenoceptors in the Normotensive Rat”, The Journal of Pharmacology andExperimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo,C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R.Stillings, “Effect of 1,4-Dioxanyl Substitution on the AdrenergicActivity of Some Standard α-Adrenoreceptor Agents”, European Journal ofMedicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C.M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M.R. Stillings & I. F. Tulloch, “Heteroaromatic Analogues of theα₂-Adrenoreceptor Partial Agonist Clonidine”, J. Med. Chem., Vol. 32(1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson,“Effects of α₂-Adrenoceptor Agonists and of Related Compounds onAggregation of, and on Adenylate Cyclase Activity in, Human Platelets”,Br. J. Pharmac., Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat.No. 5,091,528 issued to Gluchowski on Feb. 25, 1992.

Alpha-2 adrenergic agonists are useful for treating a variety ofdisorders including: respiratory disorders (e.g., asthma, nasalcongestion, COPD, cough, cystic fibrosis), gastrointestinal disorders(e.g., diahrrea, irritable bowel syndrome), ocular disorders (e.g.,glaucoma), cardiovascular disorders (e.g., myocardial ischemia, shock,arrhythmias, angina, congestive heart failure), benign prostatichypertrophy and migraine. However, many compounds disclosed in the artand related in structure to those of this invention are not alpha-2adrenoceptor selective (e.g., they interact with other alpha receptorssuch as alpha-1 adrenoceptors). Alpha-2 adrenoceptor selectivity isdesirable when treating alpha-2 associated or alpha-2 mediateddisorders. For example, alpha-2 adrenergic agonists that possesssignificant alpha-1 adrenergic effects are known to cause cardiovascularside effects such as hypertension. In addition, many compounds disclosedin the art and related in structure to those of this invention possesssignificant central nervous system (CNS) activity which may lead toundesirable side effects such as severe sedation.

It has also been observed that some alpha adrenergic agonists aresubject to extensive metabolic transformation in primates. Suchmetabolic transformation results in inactivation of the parent compoundor in the formation of an active metabolite with a differentpharmacological profile from the parent compound. Of particularimportance to the present invention is the metabolic transformation thatoccurs to some alpha adrenergic benzimidazoles that are peripherallyacting alpha-2-adrenoceptor selective agonists. Metabolic N-methylationat the benzimidazole ring may result in compounds that (1) are inactive;(2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activityat other undesired receptors, such as at alpha-1 adrenoceptors; and/or(4) have an increased potential for CNS activity. Thus, there is acontinuing need for peripherally acting selective alpha-2 adrenergiccompounds that have lower CNS activity and that resist metabolictransformation into undesirable compounds.

SUMMARY OF THE INVENTION

The present invention is directed to compounds having a structureaccording to the following formula:

wherein:

(a) R1 is alkyl;

(b) R2 is selected from the group consisting of: hydrogen, alkyl,methoxy, cyano, and halo;

(c) R3 is selected from the group consisting of: hydrogen, methyl,hydroxy, cyano and halo;

(d) R4 is selected from the group consisting of: hydrogen, methyl, ethyland isopropyl;

(e) R5 is selected from the group consisting of: hydrogen, methyl,amino, methoxy, hydroxy, cyano and halo;

(f) provided that at least one of R2, R3, R4 or R5 is other thanhydrogen or fluorine;

(g) provided that when R1 is methyl and both R2 and R5 are hydrogen, R3is other than methyl or halo;

(h) provided that when R3 is cyano, R1 is methyl; and

any tautomer of the above structure or a pharmaceutically acceptablesalt, or biohydrolyzable ester, amide, or imide thereof.

The compounds of the present invention are useful in treating manymedical disorders, including for example, respiratory disorders, oculardisorders, gastrointestinal disorders, disorders associated withsympathetic nervous system activity, migraine, peripheral pain, anddisorders where vasoconstriction would provide a benefit. Accordingly,the invention further provides pharmaceutical compositions comprisingthese compounds. The invention still further provides methods oftreatment using these compounds or the compositions containing them.

DETAILED DESCRIPTION OF THE INVENTION Terms and Definitions

“Alkyl” is an unsubstituted saturated or unsaturated hydrocarbon chainhaving 1 to 3 carbon atoms. Alkyl chains may be straight, branched orcyclized. Preferred alkyl groups are methyl, ethyl, and cyclopropyl.

“Biohydrolyzable amide” refers to an amide of a compound of theinvention that is readily converted in vivo by a subject to yield anactive compound of the invention.

“Biohydrolyzable ester” refers to an ester of a compound of theinvention that is readily converted by a subject to yield an activecompound of the invention.

“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo.Preferred halo are chloro, bromo, and iodo. More preferred halo arechloro and bromo.

“Pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987, incorporated by reference herein. Preferred cationic saltsinclude the alkali metal salts (such as sodium and potassium), alkalineearth metal salts (such as magnesium and calcium) and organic salts.Preferred anionic salts include halides, sulfonates, carboxylates,phosphates, and the like. Clearly contemplated in such salts areaddition salts that may provide an optical center, where once there wasnone. For example, a chiral tartrate salt may be prepared from thecompounds of the invention, and this definition includes such chiralsalts.

“Primate” includes humans.

Compounds

The present invention involves compounds having the following structure:

In the above structure, R1 is alkyl. Preferred R1 is methyl, ethyl orcyclopropyl.

In the above structure, R2 is hydrogen, alkyl, methoxy, cyano, or halo.Preferred R2 is hydrogen, alkyl, or cyano. More preferred R2 is methylor halo.

In the above structure, R3 is hydrogen, methyl, hydroxy, cyano or halo.Preferred R3 is cyano or hydroxy when R1 is methyl. Most preferred R3 iscyano when R1 is methyl. Preferred R3 is methyl or halo when R1 is otherthan methyl.

In the above structure, R4 is hydrogen, methyl, ethyl or isopropyl.Preferred R4 is hydrogen or methyl, more preferably hydrogen.

In the above structure, R5 is hydrogen, methyl, amino, methoxy, hydroxy,cyano or halo. Preferred R5 is hydrogen, methyl, or halo.

In the above structure, at least one of R2, R3, R4, and R5 is other thanhydrogen or fluorine. In addition, when R1 is methyl and both R2 and R5are hydrogen, then R3 is other than methyl or halo. Finally, when R3 iscyano, R1 is methyl.

The invention includes tautomers of the above structure. For example,when tautomer D of a molecule is shown (see below), it is understood toinclude tautomer E. Thus, the disclosure of one tautomeric formdiscloses each and all of the tautomers.

The invention also includes pharmaceutically acceptable acid additionsalts, biohydrolyzable esters, amides, and imides of the abovestructure.

The compounds of the invention are sufficiently basic to formacid-addition salts. The compounds are useful both in the free base formand the form of acid-addition salts, and both forms are within thepurview of the invention. The acid-addition salts are in some cases amore convenient form for use. In practice, the use of the salt forminherently amounts to the use of the base form of the active. Acids usedto prepare acid-addition salts include preferably those which produce,when combined with the free base, medicinally acceptable salts. Thesesalts have anions that are relatively innocuous to the animal organism,such as a mammal, in medicinal doses of the salts so that the beneficialproperty inherent in the free base are not vitiated by any side effectsascribable to the acid's anions.

Examples of appropriate acid-addition salts include, but at not limitedto hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate,acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate,stearate, succinate, mallate, malonate, adipate, glutarate, lactate,propionate, butyrate, tartrate, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate,cyclohexanesulfamate, and the like. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds are prepared by several methods. Forexample the free base can be dissolved in an aqueous alcohol solutioncontaining the appropriate acid and the salt is isolated by evaporationof the solution. Alternatively, they may be prepared by reacting thefree base with an acid in an organic solvent so that the salt separatesdirectly. Where separation of the salt is difficult, it can beprecipitated with a second organic solvent, or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention. All acid-addition salts are useful as sources of the freebase form, even if the particular salt per se is desired only as anintermediate product. For example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures, these salts are clearly contemplated to be a part of thisinvention.

The compounds of the invention are useful for the treatment of a varietyof diseases, disorders, and conditions that are modulated by alpha-2adrenoceptors or by alpha-2 adrenoceptor activity. As used herein, theterms “disease,” “disorder” and “condition” are used interchangeably. Asused herein, a disorder described by the terms “modulated by alpha-2adrenoceptors,” or “modulated by alpha-2 adrenoceptor activity” refersto a disorder, condition or disease where alpha-2 adrenoceptor activityis an effective means of alleviating the disorder or one or more of thebiological manifestations of the disease or disorder; or interferes withone or more points in the biological cascade either leading to thedisorder or responsible for the underlying disorder; or alleviates oneor more symptoms of the disorder. Thus, disorders subject to“modulation” include those for which:

The lack of alpha-2 activity is a “cause” of the disorder or one or moreof the biological manifestations, whether the activity was alteredgenetically, by infection, by irritation, by internal stimulus or bysome other cause;

The disease or disorder or the observable manifestation ormanifestations of the disease or disorder are alleviated by alpha-2activity. The lack of alpha-2 activity need not be causally related tothe disease or disorder or the observable manifestations thereof;

Alpha-2 activity interferes with part of the biochemical or cellularcascade that results in or relates to the disease or disorder. In thisrespect, the alpha-2 activity alters the cascade, and thus controls thedisease, condition or disorder.

The compounds of the invention are peripherally-selective alpha-2adrenoceptor agonists. Alpha-2 adrenoceptors are distributed both insideand outside of the central nervous system. Thus, for example, a compoundwhich displays a higher degree of central nervous system activity ispreferred, but not limited to, use in central nervous system indicationssuch as certain cardiovascular disorders (e.g., hypertension), pain,substance abuse and/or withdrawal. By centrally acting it is meant thatthey have some action on the alpha-2 adrenoceptors in the centralnervous system in addition to their action at peripheral alpha-2adrenoceptors.

Peripherally-acting compounds are preferred for, but not limited to, thetreatment of respiratory disorders, ocular disorders, migraine, certaincardiovascular disorders, and certain gastrointestinal disorders. Byperipherally acting, it is meant is that these compounds do not readilycross the blood-brain barrier and thus act primarily on alpha-2adrenoceptors in the periphery. In addition, further specificity ofaction of these compounds can be achieved by delivering the agent to theregion where activity is desired (for example, topical administration tothe eye, nasal mucosa or respiratory tract), thereby reducing systemicexposure. Such peripherally-selective compounds have reduced CNS sideeffect potentials, particularly with respect to sedation. Methods areavailable in the art to determine which compounds are lesscentrally-acting than others.

The compounds of the subject invention have no or only weak alpha-1agonist activity and have little or no effect on the central nervoussystem, even when dosed systemically.

Thus, the compounds of the invention are particularly useful for thetreatment of respiratory disorders including nasal congestion associatedwith allergies, colds, and other nasal disorders, (as well as thesequelae of congestion of the mucous membranes, for example, sinusitisand otitis media), cough, chronic obstructive pulmonary disease andasthma. At effective doses, it has been found that undesired sideeffects can be avoided.

The compounds of the invention are also useful for the treatment ofocular disorders such as ocular hypertension, glaucoma, hyperemia,conjunctivitis, and uveitis.

The compounds of the invention are also useful for controllinggastrointestinal disorders, such as diarrhea, irritable bowel syndrome,hyperchlorhydria and peptic ulcer.

The compounds of the invention are also useful for diseases anddisorders associated with sympathetic nervous system activity, includinghypertension, myocardial ischemia, cardiac reperfusion injury, angina,cardiac arrhythmia, heart failure and benign prostatic hypertrophy.

The compounds of the invention are also useful for the prophylactic oracute treatment of migraine.

The compounds of the invention are also useful for the treatment ofperipheral pain states associated with various disorders (for example,peripheral neuralgia).

The compounds of the invention are also useful for other diseases anddisorders where vasoconstriction, particularly of veins, would provide abenefit, including septic or cardiogenic shock, elevated intracranialpressure, hemmorhoids, venous insufficiency, varicose veins, andmenopausal flushing.

The pharmacological activity and selectivity of these compounds can bedetermined using published test procedures. The alpha-2 selectivity ofthe compounds is determined by measuring receptor binding affinities andin vitro functional potencies in a variety of tissues known to possessalpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 AdrenergicReceptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) Thefollowing in vivo assays are typically conducted in rodents or otherspecies. Central nervous system activity is determined by measuringlocomotor activity as an index of sedation. (See, e.g., Spyraki, C. & H.Fibiger, “Clonidine-induced Sedation in Rats: Evidence for Mediation byPostsynaptic Alpha-2 Adrenoreceptors”, Journal of Neural Transmission,Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measuredusing rhinomanometry as an estimate of nasal airway resistance. (See,e.g., Salem, S. & E. Clemente, “A New Experimental Method for EvaluatingDrugs in the Nasal Cavity”, Archives of Otolaryngology, Vol. 96 (1972),pp. 524-529). Antiglaucoma activity is determined by measuringintraocular pressure. (See, e.g., Potter, D., “Adrenergic Pharmacologyof Aqueous Human Dynamics”, Pharmacological Reviews, Vol. 13 (1981), pp.133-153). Antidiarrheal activity is determined by measuring the abilityof the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g.,Thollander, M., P. Hellstrom & T. Svensson, “Suppression of CastorOil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists”, AlimentaryPharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy intreating irritable bowel syndrome is determined by measuring the abilityof compounds to reduce the stress-induced increase in fecal output.(See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro &H. Ormsbee III, “Cold-restraint stress increases rat fecal pellet outputand colonic transit”, American Journal of Physiology, Vol. 258 (1990),pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy isdetermined by measuring the reduction in gastric acid secretion producedby these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca &C. Roze, “Effect of α2-adrenoceptor agonists on gastric pepsin and acidsecretion in the rat”, British Journal of Pharmacology, Vol. 106 (1992),pp. 790-796). Antiasthma activity is determined by measuring the effectof the compound on bronchoconstriction associated with pulmonarychallenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser &J. Hand, “Effects of a Novel Leukotriene D₄ Antagonist with5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, onLeukotriene-D₄- and Antigen-Induced Bronchoconstriction in Guinea Pig”,International Archives of Allergy and Applied Immunology, Vol. 86(1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B.Marchette, J. Stevenson & W. Abraham, “The Role of Slow-ReactingSubstance of Anaphylaxis in the Late Bronchial Response After AntigenChallenge in Allergic Sheep”, American Reviews of Respiratory Disease,Vol. 130 (1984), pp. 748-754). Activity in cough is determined bymeasuring the number and latency of the cough response to respiratorychallenges such as inhaled citric acid. (See, e.g., Callaway, J. & R.King, “Effects of Inhaled α2-Adrenoceptor and GABA_(B) Receptor Agonistson Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs”,European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). Thesympatholytic activity of these compounds is determined by measuring thereduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo & K.Starke “Involvement of peripheral presynaptic inhibition in thereduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304”,European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or thereduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S.Carlsson, P. Thoren & T. Hedner, “Effects of clonidine on renalsympathetic nerve -activity, natriuresis and diuresis in chroniccongestive heart failure rats”, Journal of Pharmacology and ExperimentalTherapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis fortheir benefit in heart failure and benign prostatic hypertrophy. Thehypotensive effect of these compounds is measured directly as areduction in mean blood pressure (See, e.g., Timmermans, P. & P. VanZwieten, “Central and peripheral α-adrenergic effects of someimidazolidines”, European Journal of Pharmacology, Vol. 45 (1977), pp.229-236). Clinical studies have demonstrated the beneficial effect ofalpha-2 agonists in the prevention of myocardial ischemia during surgery(See, e.g., Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M.Hollenberg & D. Mangano, “Effects of Perioperative DexmedetomidineInfusion in Patients Undergoing Vascular Surgery”, Anesthesiology, Vol.82 (1995), pp. 620-633) and in the prevention of angina (See, e.g.,Wright, R. A., P. Decroly, T. Kharkevitch & M. Oliver, “ExerciseTolerance in Angina is Improved by Mivazerol—an α2-AdrenoceptorAgonist”, Cardiovascular Drugs and Therapy, Vol. 7 (1993), pp. 929-934).The efficacy of these compounds in cardiac reperfusion injury isdemonstrated by measuring the reduction of cardiac necrosis andneutrophil infiltration (See, e.g., Weyrich, A., X. Ma, & A. Lefer, “TheRole of L-Arginine in Ameliorating Reperfusion Injury After MyocardialIschemia in the Cat”, Circulation, Vol. 86 (1992), pp. 279-288). Thecardiac antiarrhythmic effect of these compounds is demonstrated bymeasuring the inhibition of ouabain induced arrhythmias (See, e.g.,Thomas, G. & P. Stephen, “Effects of Two Imidazolines (ST-91 and ST-93)on the Cardiac Arrhythmias and Lethality Induced by Ouabain inGuinea-Pig”, Asia-Pacific Journal of Pharmacology, Vol. 8 (1993),pp.109-113; and Samson, R., J. Cai, E. Shibata, J. Martins & H. Lee,“Electrophysiological effects of α2-adrenergic stimulation in caninecardiac Purkinje fibers”, American Journal of Physiology, Vol. 268(1995), pp. H2024-H2035). The vasoconstrictor activity of thesecompounds is demonstrated by measuring the contractile properties onisolated arteries and veins in vitro (See, e.g., Flavahan, N., T.Rimele, J. Cooke & M. Vanhoutte, “Characterization of PostjunctionalAlpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous orNerve-Released Norepinephrine in the Canine Saphenous Vein”, Journal ofPharmacology and Experimental Therapeutics, Vol. 230 (1984), pp.699-705). The effectiveness of these compounds at reducing intracranialpressure is demonstrated by measurement of this property in a caninemodel of subarachnoid hemorrhage (See, e.g., McCormick, J., P.McCormick, J. Zabramski & R. Spetzier, “Intracranial pressure reductionby a central alpha-2 adrenoreceptor agonist after subarachnoidhemorrhage”, Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibitionof menopausal flushing is demonstrated by measuring the reduction offacial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H.Connor & S. Brain, “The modulation of the increase in rat facial skinblood flow observed after trigeminal ganglion stimulation”, EuropeanJournal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated foralpha-2 adrenergic agonists on cutaneous blood flow in the tail (See,e.g., Redfern, W., M. MacLean, R. Clague & J. McGrath, “The role ofalpha-2 adrenoceptors in the vasculature of the rat tail”, BritishJournal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). Theantimigraine effect of these compounds is demonstrated by measuring thereduction of dural neurogenic inflammation to trigeminal ganglionstimulation in the rat (See, e.g., Matsubara, T., M. Moskowitz & Z.Huang, “UK-14,304, R(−)-alpha-methyl-histamine and SMS 201-995 blockplasma protein leakage within dura mater by prejunctional mechanisms”,European Journal of Pharmacology, Vol. 224 (1992), pp. 145-150).

Metabolic Stability

It has been observed that some peripherally acting, alpha-2-selectiveadrenergic agonist benzimidazoles which appear metabolically stable invitro and in vivo in rodents, are subject to metabolic transformation inprimates (i.e., monkeys and humans) via N-methylation at thebenzimidazole ring. Such metabolic transformation has been shown toalter the profile of these benzimidazoles such that they may bemetabolized into compounds that (1) are inactive; (2) are alpha-2adrenoceptor antagonists; (3) possess enhanced activity at otherundesired receptors, such as at alpha-1 adrenoceptors; and/or (4) havean increased potential for CNS activity. The compounds of the presentinvention are peripherally acting selective alpha-2 adrenergic compoundsthat have lower CNS activity and that resist metabolic transformationinto such undesirable compounds.

Metabolic stability of the compounds described above is evaluated invitro in a precision cut liver slice assay and in vivo inpharmacokinetic studies in primates. The precision cut liver slice assayis a well recognized, validated in vitro model to study xenobioticmetabolism in animal species and humans. (See Ekins, S. “Past, present,and future applications of precision-cut liver slices for in vitroxenobiotic metabolism.” (Department of Medicine and Therapeutics,University of Aberdeen, UK.) Drug-Metab-Rev. (November, 1996) Vol. 28,No. 4: pp. 591-623). This assay is used to evaluate the metabolicactivity of alpha-2 adrenergic agonists. The assay provides data on thebiotransformations taking place within intact hepatocytes of the speciesof interest. Thus the full compliment of phase I and phase II metabolicenzymes are available to metabolize the drug as is the case in vivo.

For the pharmacokinetic studies, the compounds are administered orallyto cynomolgus monkeys and measurements of administered benzimidazolecompounds and corresponding N-methyl metabolites are made using 100 μLaliquots of urine collected over various time-periods post-dose.Typically, a chemical homolog or stable-isotope-labeled internalstandard is added to each sample and then diluted 100× in water. Ten μLof prepared sample is then analyzed by gradient HPLC, with tandem massspectrometry detection. Single ion reaction monitoring schemes areemployed to selectively detect the test compound, its N-methylmetabolite (if present), and the internal standard.

The compounds of the present invention show little to no metabolicN-methylation in these assays. In contrast, N-methyl metabolites werefound for other alpha-2 selective benzimidazole compounds such as5-(2-Imidazolinylamino)-4-methylbenzimidazole and4-ethyl-5-(2-imidazolinylamino)benzimidazole.5-(2-Imidazolinylamino)-4-methylbenzimidazole provides a very similarpharmacological profile to7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole (see Example 1below). That is, both compounds are very potent and selective alpha-2adrenergic agonists, with very low CNS activity. In the precision cutliver slice assay, there is no evidence of the methyl metabolite for7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole. However,5-(2-imidazolinylamino)-4-methylbenzimidazole, is rapidly metabolized inthis assay and it was found that its metabolite is an alpha-2 adrenergicagonist with a significantly higher potential for CNS activity than theparent compound. 4-ethyl-5-(2-imidazolinylamino)benzimidazole, anotherselective alpha-2 adrenergic agonist, is rapidly and extensivelyN-methylated in primates. Its metabolite is a very potent alpha-2antagonist, rather than an alpha-2 agonist.

The results indicate that the metabolic transformation of benzimidazolesthrough N-methylation can lead to rapid formation of undesiredmetabolites that have different pharmacological effects relative to theparent compound and that these effects are not easily predictable.Without being bound by theory it is contemplated that the factorfavorably affecting the metabolic stability of the benzimidazolecompounds of this invention is the sterical hindrance provided bysubstituents in close proximity to the benzimidazole nitrogens.

The compounds of this invention can be made using conventional organicsyntheses. Particularly preferred syntheses are carried out using thefollowing general schemes, Schemes 1-5. In the following generalreaction schemes, R1, R2, R3, R4, and R5 are as defined above. Forclarity, R1, R2, R3, R4, and/or R5 do not appear on the intermediateswithin a specific scheme unless they are prepared or needed in thatspecific scheme. Preferably, R₁ is part of the starting material (seeScheme 1). R2 can be part of the starting material or introduced viaamination or bromination followed by functional group manipulation (seeScheme 2). R3 can be part of the starting material (see Scheme 1) orobtained by manipulation of a carboxylic acid (see Scheme 3). R4 isintroduced by alkylation of an aniline substrate prior to thebenzimidazole ring formation (see Scheme 1). R5 or a direct precursor toR5 is introduced during the benzimidazole ring formation (see Scheme 4).Finally, the 5-(2-imidazolinylamino) group is conveniently obtained fromthe aminobenzimidazoles prepared according to Schemes 1-4 (see Scheme5).

The starting materials depicted within the schemes are commerciallyavailable or are made from commercially available starting materials andmethods known to one of ordinary skill in the art. The skilled artisanmay change temperature, pressure, atmosphere, solvents, or the order ofreactions as appropriate. Additionally, the skilled artisan may useprotecting groups to block side reactions or increase yields asappropriate. All such modifications can be readily be carried out by theskilled artisan in the art of organic chemistry, and thus are within thescope of the invention.

EXAMPLES

The following non-limiting examples illustrate the compounds of thepresent invention.

Example 1

7-Cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole

2,6-Dinitro-P-toluic acid. To a 500 mL roundbottom flask is added 120 mLof concentrated sulfuric acid. This is cooled to 0° C. and to this isadded p-toluic acid (30 g, 0.22 mole). To this mixture is slowly added amixture of fuming nitric acid (25 mL) and concentrated sulfuric acid(100 mL) via an addition funnel. The resulting mixture is then stirredat 0° C. for 10 minutes, slowly warmed first to room temperature, thento 90° C. for 1.5 hours. The mixture is cooled to room temperature andpoured into ice/water. The resulting solid is then filtered and dried toafford 2,6-dinitro-p-toluic acid as an off-white solid.

2.6-Dinitro-p-toluic carboxamide. A mixture of 2,6-dinitro-p-toluic acid(15.14 g, 66.9 mmol) and sulfamide (14.79 g, 153.8 mmol) in anhydrouspyridine (80 mL) is stirred under an argon atmosphere at 100° C. for 3hours. The mixture is poured into ice/water and the resultingprecipitate is filtered and washed with water to afford2,6-dinitro-p-toluic carboxamide as an off-white solid.

3-Amino-2,6-dinitro-p-toluic carboxamide. To a 1 L 3-neck round bottomflask equipped with a mechanical stirrer, are placed2,6-dinitro-p-toluic carboxamide (4.0 g, 18 mmol) and hydroxylaminehydrochloride (3.3 g, 48 mmol) in ethanol (550 mL) and water (24 mL).The mixture is cooled to 0° C. and treated dropwise with a saturatedsolution of potassium hydroxide in methanol (80 mL) over a period of 1.5hours. The resulting mixture is poured into a 2 L round bottom flask anddiluted with 400 mL of water. The methanol and ethanol are then removedvia rotary evaporation. A yellow precipitate formed which is filtered togive rise to 3-amino-2,6-dinitro-p-toluic carboxamide as fine yellowneedles.

2,3-Diamino-6-nitro-p-toluic carboxamide. To a mixture of3-amino-2,6-dinitro-p-toluic carboxamide (2.2 g, 9.2 mmol) in ethanol(200 mL) at 80° C. is added dropwise a solution of sodium sulfide (2.2g, 28 mmol) in water (80 mL) over a period of one hour. The mixture isstirred at 80° C. for another 2 hours, then allowed to cool to roomtemperature and poured into ice. The mixture is extracted with ethylacetate (5×300 mL). The combined extracts are dried over magnesiumsulfate and rotary evaporated to give rise to2,3-diamino-6-nitro-p-toluic carboxamide as a red/brown solid. Thecompound is used in the next step without further purification.

7-(4-Methyl-5-nitrobenzimidazolyl)carboxamide. A solution of2,3-diamino-6-nitro-p-toluic carboxamide (1.49 g, 7.1 mmol) in formicacid (10 mL) is stirred at 100° C. for two hours. The solution is cooledto room temperature and poured into ice and basified to pH=10 withconcentrated ammonium hydroxide. A brown precipitate forms which isfiltered to afford 7-(4-methyl-5-nitrobenzimidazolyl)carboxamide as atan solid.

7-Cyano-4-methyl-5-nitrobenzimidazole. A mixture of7-(4-methyl-5-nitrobenzimidazolyl)carboxamide (1.5 g, 7.0 mmol) inphosphorous oxychloride (20 mL) and toluene (20 mL) is heated to refluxunder an argon atmosphere for two hours. The mixture is cooled to roomtemperature, poured into ice and basified to pH=10 with concentratedammonium hydroxide. The resulting mixture is extracted with 3:1methylene chloride/isopropyl alcohol (6×100 mL), and the combinedextracts dried over magnesium sulfate and rotary evaporated. The residueis purified by flash chromatography on silica gel, eluting with 9:1:0.1chloroform:methanol:ammonium hydroxide to afford7-cyano-4-methyl-5-nitrobenzimidazole as a yellow solid.

5-Amino-7-cyano-4-methylbenzimidazole. A mixture of7-cyano-4-methyl-5-nitrobenzimidazole (0.91 g, 4.5 mmol) and 10%palladium-on-carbon (100 mg) in methanol (200 mL) is treated with anatmosphere of hydrogen (1 atm, balloon) for 14 hours. The resultingmixture is filtered through Celite and rotary evaporated. The residue ispurified by flash chromatography (silica gel, 95:5 ethylacetate:methanol) to afford 5-amino-7-cyano-4-methylbenzimidazole.

7-Cyano-5-isothiocyanato-4-methylbenzimidazole. To a solution ofdi-2-pyridylthionocarbonate (1.02 g, 3.1 mmol) and4-dimethylaminopyridine (25 mg, 0.21 mmol) in tetrahydrofuran (350 mL)is added dropwise a solution of 5-amino-7-cyano-4-methylbenzimidazole(0.36 g, 2.1 mmol) in tetrahydrofuran (50 mL). The solution is stirredfor one hour at room temperature. The reaction mixture is rotaryevaporated and the residue is purified by flash chromatography (silicagel, 100% ethyl acetate) to give7-cyano-5-isothiocyanato-4-methylbenzimidazole as an off-white solid.

N-5-(7-Cyano-4-methylbenzimidazolyl)-N′-2-aminoethylthiourea. A solutionof 7-cyano-5-isothiocyanato-4-methylbenzimidazole (0.29 g, 1.35 mmol) intetrahydrofuran (30 mL) is added dropwise to a solution ofethylenediamine (0.41 g, 6.8 mmol) in tetrahydrofuran (30 mL). A whiteprecipitate forms after the solution has stirred at room temperature for15 minutes. The reaction mixture is rotary evaporated to affordN-5-(7-cyano-4-methylbenzimidazolyl)-N′-2-aminoethylthiourea as anoff-white solid.

7-Cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole. To a 500 mL roundbottom flask are added methanol (150 mL) andN-5-(7-cyano-4-methylbenzimidazolyl)-N′-2-aminoethylthiourea (0.31 g,1.1 mmol). This mixture is heated slightly with a heat gun to provide ahomogeneous mixture. To this mixture is added mercuric acetate (0.39 g,1.2 mmol). The resulting mixture is stirred for 4 hours at roomtemperature then filtered through Celite and concentrated to afford7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole as a white foam.

Example 2

4-Ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole

3-(1-Hydroxyethyl)-6-methylaniline. To an ice-cold solution of4-methyl-3-nitroacetophenone (25 g, 139 mmol) in methanol (200 mL) isadded sodium borohydride (6.2 g, 163 mmol) over 15 minutes. The mixtureis stirred at room temperature for 1 hour, then is quenched with water.The mixture is rotary evaporated and the residue is partitioned betweenwater and ethyl acetate. The organic layer is dried (magnesium sulfate)and rotary evaporated to afford a light brown viscous oil. The oil isdiluted with ethyl acetate (200 mL), 5% palladium-on-carbon (5 g) isadded and the mixture is treated with hydrogen at 40 psi for 18 hours.The mixture is then filtered on Celite and the filtrate is rotaryevaporated to afford 3-(1-hydroxyethyl)-6-methylaniline as a lightyellow, pasty solid.

3-Ethyl-6-methylacetanilide. A mixture of3-(1-hydroxyethyl)-6-methylaniline (21.3 g, 139 mmol), acetic anhydride(28 mL, 296 mmol), triethylamine (41 mL, 296 mmol) and4-dimethylaminopyridine (0.5 g, 4 mmol) in methylene chloride (200 mL)is stirred at room temperature for 3 hours. Methanol (50 mL) is addedand the mixture is rotary evaporated. The residue is partitioned betweenwater and ethyl acetate. The organic layer is washed with water, 1Nhydrochloric acid, water and brine, then dried (magnesium sulfate) androtary evaporated. The residue is diluted with trifluoroacetic acid (100mL) and cooled in an ice bath. Diethylsilane (35 mL, 270 mmol) is addedand the resulting mixture is stirred at room temperature for 2 hours.The mixture is rotary evaporated and the residue is purified by flashchromatography on silica gel (hexane:ethyl acetate 3:1) to afford3-ethyl-6-methylacetanilide as a foamy white solid.

2,4-Dinitro-3-ethyl-6-methylacetanilide. To an ice-cold mixture of3-ethyl-6-methylacetanilide (11.5 g, 64.8 mmol) in conc. sulfuric acid(90 mL) is slowly added fuming nitric acid (7 mL). The mixture isstirred for 30 minutes in the ice bath, then for 1 hour at roomtemperature. The mixture is poured into ice and the solid that forms iscollected by filtration, washed with water and dried under vacuum. Themixture of 2,4-dinitro-3-ethyl-6-methylacetanilide and4,5-dinitro-3-ethyl-6-methylacetanilide is separated by flashchromatography on silica gel (hexane:ethyl acetate gradient 4:1 to 2:3).

2,4-Dinitro-3-ethyl-6-methylaniline. A mixture of2,4-dinitro-3-ethyl-6-methylacetanilide (4.0 g, 14.9 mmol), potassiumcarbonate (2.6 g, 19 mmol) and 6N hydrochloric acid (40 mL) in methanol(100 mL) is heated to reflux for 2 hours. The mixture is cooled to roomtemperature, brought to pH 9 with ammonium hydroxide and rotaryevaporated. The residue is purified by flash chromatography on silicagel (chloroform:methanol 9:1) to afford2,4-dinitro-3-ethyl-6-methylaniline as a yellow solid.

4-Ethyl-5-formamido-7-methylbenzimidazole. A mixture of2,4-dinitro-3-ethyl-6-methylaniline (2.0 g, 8.9 mmol) and iron powder(5.0 g, 90 mmol) in 90% formic acid (36 mL) is heated to reflux for 18hours. The mixture is cooled to room temperature, diluted with methanol(75 mL) and filtered through Celite. The filtrate is rotary evaporatedand the residue is purified by flash chromatography on silica gel(chloroform:methanol 9:1) to afford4-ethyl-5-formamido-7-methylbenzimidazole as a tan solid.

5-Amino-4-ethyl-7-methylbenzimidazole. A mixture of4-ethyl-5-formamido-7-methylbenzimidazole (1.7 g, 8.36 mmol), potassiumcarbonate (2.0 g, 14.4 mmol) and 6N hydrochloric acid (34 mL) inmethanol (34 mL) is heated to reflux for 1 hour. The mixture is cooledto room temperature, brought to pH 9 with ammonium hydroxide and rotaryevaporated. The residue is purified by flash chromatography on silicagel (chloroform:methanol 9:1) to afford5-amino-4-ethyl-7-methylbenzimidazole as a tan solid.

4-Ethyl-5-isothiocyanato-7-methylbenzimidazole. To a mixture ofdi-2-pyridyl thionocarbonate (0.72 g, 3.11 mmol) and4-dimethylaminopyridine (0.02 g) in ethyl acetate (50 mL) is addeddropwise a solution of 5-amino-4-ethyl-7-methylbenzimidazole (0.42 g,2.39 mmol) in ethyl acetate (20 mL) and methanol (5 mL). The mixture isstirred at room temperature for 3 hours, then rotary evaporated. Theresidue is purified by filtration on a short pad of silica gel, elutingwith ethyl acetate, to afford4-ethyl-5-isothiocyanato-7-methylbenzimidazole as a tan solid.

4-Ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole, trifluoroaceticacid salt. To a mixture of ethylenediamine (0.65 mL, 9.66 mmol) inmethylene chloride (50 mL) is added a suspension of4-ethyl-5-isothiocyanato-7-methylbenzimidazole (0.42 g, 1.93 mmol) inmethylene chloride (50 mL). The mixture is stirred for 1 hour at roomtemperature, then rotary evaporated. The residue is diluted withmethanol (100 mL) and mercuric acetate (0.74 g, 2.32 mmol) is added. Themixture is stirred at room temperature for 2 hours. The mixture isfiltered on Celite with a methanol wash of the solids. The filtrate isrotary evaporated and the reside is purified by preparative HighPressure Liquid Chromatography (HPLC) (C18 column; flow rate 45 mL/min;solvent gradient: 0.1% trifluoroacetic acid (in water)/acetonitrilestarting at 95/5 and going to 0/100 over 45 minutes) to afford4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole as atrifluoroacetic acid salt.

Example 3

4-Cyclopropyl-5-(2-imidazolinylamino)-7-methylbenzimidazole

Commercially available 1-(4-methylphenyl)-1-cyclopropane carboxylic acidis treated with nitronium tetrafluoroborate in sulfolane to afford1-(4-methyl-3-nitrophenyl)-1-cyclopropane carboxylic acid. This isconverted to 1-(4-methyl-3-nitrophenyl)-1-bromocyclopropane by treatmentwith mercuric oxide and bromine in methylene chloride. Reduction withzinc dust in the presence of calcium chloride in aqueous ethanol affords5-cyciopropyl-2-methylaniline. Conversion to4-cyclopropyl-5-(2-imidazolinylamino)-7-methylbenzimidazole is completedin the same manner as4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole (see Example 2).

Example 4

7-Hydroxy-5-(2-imidazolinylamino)-4-methylbenzimidazole

(2-imidazolinylamino)-7-methoxy-4-methylbenzimidazole is made in thesame manner as 4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazoleexcept that 2-methoxy-5-methylacetanilide is used instead of3-ethyl-6-methylacetanilide (see Example 2). Cleavage of the methylether is achieved with pyridinium hydrochloride to afford7-hydroxy-5-(2-imidazolinylamino)-4-methylbenzimidazole.

Example 5

4,6-Dimethyl-5-(2-imidazolinylamino)benzimidazole

5-Chloro-2,4-dinitro-m-xylene. To ice cold concentrated sulfuric acid isadded 5-chloro-m-xylene (10.0 g, 71 mmol). With vigorous stirring, solidpotassium nitrate (14.35 g, 0.14 mol) is added slowly over 30 minutes.Upon completion of addition, the reaction mixture is warmed to roomtemperature and stirred for 2 hours. The solid that has formed isfiltered and recrystallized from ethanol/water. This material is furtherpurified by flash chromatography on silica gel (95:5 hexane:ethylacetate) to afford 5-chloro-2,4-dinitro-m-xylene as a white crystallinesolid.

5-Azido-2,4-dinitro-m-xylene. A mixture of 5-chloro-2,4-dinitro-m-xylene(707 mg, 3.1 mmol), sodium azide (219 mg, 3.37 mmol) andN,N-dimethylformamide (10 mL) is heated at 80° C. for 45 minutes thencooled to room temperature, poured into ice/water and extracted withethyl acetate (3×50 mL). The combined organic layers are dried(magnesium sulfate), filtered, and concentrated via rotary evaporationto provide 5-azido-2, 4-dinitro-m-xylene as a yellow/brown solid. (650mg, 2.7 mmol), 10% palladium-on-carbon (100 mg) and 80% formic acid (20mL) is heated to 80° C. for 30 minutes, cooled to room temperature, andfiltered through a plug of silica gel (eluting with water). The filtrateis basified (˜pH 10) with 28% ammonium hydroxide and extracted withethyl acetate (3×100 mL). The combined organic layers are dried(magnesium sulfate), filtered, and concentrated to afford4,6-dimethyl-5-nitrobenzimidazole as a yellow oil.

5-Amino-4,6-dimethylbenzimidazole. A heterogeneous mixture of4,6-dimethyl-5-nitrobenzimidazole (410 mg, 2.14 mmol) and 10%palladium-on-carbon (50 mg) in methanol (25 mL) is treated with anatmosphere of hydrogen (1 atm, balloon) for 16 hours. The resultingmixture is filtered through Celite and rotary evaporated. The residue ispurified by chromatography on silica gel (95:5 methylenechloride:methanol) to afford 5-amino-4,6-dimethylbenzimidazole as awhite solid.

4,6-Dimethyl-5-isothiocyanatobenzimidazole. A mixture of5-amino-4,6-dimethylbenzimidazole (265 mg, 1.64 mmol), tetrahydrofuran(20 mL), di-2-pyridylthionocarbonate (584 mg, 1.81 mmol), and4-dimethylaminopyridine (20 mg, 0.016 mmol is stirred at roomtemperature for 2 hours. The mixture is rotary evaporated and theresidue is purified by chromatography on silica gel (50:50 hexane:ethylacetate) to provide 4,6-dimethyl-5-isothiocyanatobenzimidazole as anoff-white solid.

4,6-Dimethyl-5-(2-imidazolinviamino)benzimidazole. A solution of4,6-dimethyl-5-isothiocyanatobenzimidazole (250 mg, 1.23 mmol) inmethylene chloride (5 mL) is added dropwise to a solution ofethylenediamine (370 mg, 6.2 mmol) in methylene chloride (5 mL). Theresulting solution is stirred at room temperature for 15 minutes thenrotary evaporated. The residue is dissolved in methanol (10 mL) and tothis solution is added mercuric acetate (390 mg, 1.23 mmol). Theresulting reaction mixture is stirred at room temperature for 1 hour,filtered through a pad of silica gel and rotary evaporated. The residueis purified by chromatography on silica gel (70:30:0.5 methylenechloride:methanol:ammonium hydroxide) to afford4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole as a white solid.

Example 6

6-Bromo-5-(2-imidazolinylamino)-4-methylbenzimidazole

Commercially available 2,6-dinitrotoluene is converted to5-amino-4-methylbenzimidazole according to scheme 1. Bromination isachieved by treatment with bromine in acetic acid. The synthesis is thencompleted according to Scheme 5.

Example 7

7-Cyano-1,4-dimethyl-5-(2-imidazolinylamino)benzimidazole

This compound is made according to a combination of Schemes 1 and 3using 3-amino-2,6-dinitro-p-toluic carboxamide as prepared in Example 1.

Example 8

1,7-Dimethyl-4-ethyl-5-(2-imidazolinylamino)benzimidazole

This compound is made according to Scheme 1.2,4-Dinitro-3-ethyl-6-methylaniline is treated with paraformaldehyde inconcentrated sulfuric acid to affordN-methyl-2,4-dinitro-3-ethyl-6-methylaniline. The synthesis is completedin the same manner as 4-ethyl-5-(2-imidazolinylamino)benzimidazole (seeExample 2).

Example 9

2,4-Dimethyl-5-(imidazolinylamino)benzimidazole

2,3-diamino-6-nitrotoluene. To a solution 3-methyl-2,4-dinitroaniline(30 g) in boiling ethanol (750 mL) is added dropwise over 90 minutes asolution of sodium sulfide nonahydrate (109.6 g) in water (750 mL). Atthe end of the addition, the mixture is heated to reflux for 30 minutesthen poured into ice (2000 g) and allowed to stand until all the ice hasmelted. The mixture is then extracted with methylene chloride and theorganic layer is dried over magnesium sulfate and rotary evaporated. Theresidue is purified by flash chromatography on silica get, eluting withmethylene chloride to afford 2,3-diamino-6-nitrotoluene as an orangesolid.

2,4-Dimethyl-5-nitrobenzimidazole. A mixture of2,3-diamino-6-nitrotoluene (0.945 g, 5.65 mmol), conc. hydrochloric acid(5 mL) and glacial acetic acid (30 mL) is heated to reflux for 2 hours.The mixture is cooled to room temperature, then poured in a mixture ofcrushed ice (100 mL) and ammonium hydroxide (100 mL) and extracted with20% methanol in chloroform (2×400 mL). The combined extracts are driedover potassium carbonate and rotary evaporated to afford2,4-dimethyl-5-nitrobenzimidazole as a brown solid. The product is usedin the following step without further purification.

1-t-Butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole. A mixture of2,4-methyl-5-nitrobenzimidazole (0.63 g, 4.3 mmol),di-t-butyl-dicarbonate (0.24 g, 10.8 mmol), triethylamine (0.725 mL, 5.2mmol) and 4-dimethylaminopyridine (0.05 g) in ethyl acetate (45 mL) isstirred at room temperature overnight. The mixture is rotary evaporatedand the residue purified by flash chromatography on silica gel, elutingwith 10% ethyl acetate in hexane to afford1-t-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole as a white solid.

5-Amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole. To a solution of1-t-butoxycarbonyl-2,4-dimethyl-5-nitrobenzimidazole (1.26 g, 4.32 mmol)in methanol (15 mL)/ethyl acetate (100 mL) are added 10%palladium-on-carbon (0.1 g) and ammonium formate (1.09 g, 17.3 mmol).The mixture is stirred at room temperature for 3 hours, then filtered onCelite with a methanol wash of the solids. The filtrate is rotaryevaporated and the residue is purified by flash chromatography on silicagel, eluting with 20% ethyl acetate in hexane to afford5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole as a white solid.

1-t-Butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole. Asolution of 5-amino-1-t-butoxycarbonyl-2,4-dimethylbenzimidazole (1.1 g,4.2 mmol) in methylene chloride (60 mL) is added dropwise over 30minutes to a solution of di-2-pyridyl thionocarbonate (1.9 g, 8.2 mmol)and 4-dimethylaminopyridine (0.1 g) in methylene chloride (150 mL). Themixture is stirred for 2 hours at room temperature then rotaryevaporated. The residue is purified by flash chromatography on silicagel, eluting with 10% ethyl acetate/hexane to afford1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole as a whitesolid.

N-(1-t-Butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthiourea.A solution of1-t-butoxycarbonyl-2,4-dimethyl-5-isothiocyanatobenzimidazole (1.15 g,3.8 mmol) in methylene chloride (100 mL) is added dropwise over 15minutes to 1,2-ethylenediamine (1.26 mL, 18.9 mmol) in solution inmethylene chloride (200 mL). The mixture is stirred for 2 hours at roomtemperature. The mixture is rotary evaporated and the residue istriturated with ether (150 mL) for 1 hour at room temperature. The solidis filtered and dried in vacuo to affordN-(1-t-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthioureaas a white solid.

2,4-Dimethyl-5-(2-imidazolinviamino)benzimidazole. A mixture ofN-(1-t-butoxycarbonyl-2,4-dimethyl-5-benzimidazolyl)-N′-2-aminoethylthiourea(1.33 g, 3.66 mmol) and mercuric acetate (1.45 g, 4.54 mmol) in methanol(150 mL) is stirred at room temperature for 1 hour. The resulting blackmixture is filtered on Celite with a methanol wash of the solids. Thefiltrate is rotary evaporated and the residue is purified by flashchromatography on a short pad of silica gel, eluting with 10%methanol/chloroform containing 1% of ammonium hydroxide. Theproduct-containing fractions are collected and rotary evaporated toafford 2,4-dimethyl-5-(2-imidazolinylamino)benzimidazole as a whitesolid.

Example 10

7-Cyano-2,4-dimethyl-5-(2-imidazolinylamino)benzimidazole

This compound is made according to Scheme 4 from3-amino-2,6-dinitro-p-toluic carboxamide prepared in Example 1.

Example 11

2-Amino-4,6-dimethyl-5-(2-imidazolinylamirio)benzimidazole

N-Acetyl-3,5-dimethylaniline. A mixture of 3,5dimethylaniline (20 g, 165mmol), acetic anhydride (24 mL, 247 mmol) and triethylamine (70 mL, 495mmol) in methylene chloride (300 mL is stirred at room temperature for16 hours. The mixture is washed with water, dried (magnesium sulfate)and rotary evaporated. The residue is triturated with hexane andfiltered to afford N-acetyl-3,5-dimethylaniline (25 g).

N-Acetyl-3,5-dimethyl-2,4-dinitroaniline. To a cold (ice) solution ofN-acetyl-3,5-dimethylaniline (25 g, 153 mmol) in concentrated sulfuricacid (500 mL) is added potassium nitrate (48 g, 474 mmol). The mixtureis stirred for 45 minutes at 0° C. then 15 hours at room temperature.The mixture is poured into ice/water and extracted with chloroform. Theextract is dried (magnesium sulfate) and rotary evaporated. The residueis purified by flash chromatography on silica gel (30% ethylacetate/hexane) to afford N-acetyl-3,5-dimethyl-2,4-dinitroaniline (14.6g).

3,5-Dimethyl-2,4-dinitroaniline. A mixture ofN-acetyl-3,5-dimethyl-2,4-dinitroaniline (14.6 g, 57 mmol) and sodiummethoxide (25 wt % solution in methanol) (26 mL) and methanol (200 mL)is heated to reflux for 90 minutes. The mixture is rotary evaporated andthe residue is partitioned between water and chloroform. The organiclayer is dried (magnesium sulfate) and rotary evaporated. The residue ispurified by flash chromatography on silica gel (25% ethylacetateihexane) to afford 3,5-dimethyl-2,4-dinitroaniline (8.0 g) as anorange solid.

1,2-Diamino-3,5-dimethyl-4-nitrobenzene. A solution of3,5-dimethyl-2,4-dinitroaniline (1.5 g, 7 mmol) in ethyl acetate (100mL) is treated with hydrogen at atmospheric pressure for 2 hours. Themixture is filtered on Celite and the filtrate is rotary evaporated toafford 1,2-diamino-3,5-dimethyl4-nitrobenzene (1.25 g) as a red solid.

2-Amino-4,6-dimethyl-5-nitrobenzimidazole. A mixture of1,2-diamino-3,5-dimethyl-4-nitrobenzene (0.87 g, 4.83 mmol) and cyanogenbromide (0.87 g, 7.73 mmol) in methanol (50 mL) is stirred at roomtemperature for 16 hours. The mixture is rotary evaporated to afford2-amino-4,6-dimethyl-5-nitrobenzimidazole. The product is used in thenext step without further purification.

2-(t-Butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole. A mixtureof 2-amino-4,6-dimethyl-5-nitrobenzimidazole (1.3 g, 6.31 mmol),di-t-butyl dicarbonate (2.5 mL of 1M solution in tetrahydrofuran, 7.56mmol), triethylamine (2.6 mL, 18.9 mmol) and dimethylaminopyridine (0.1g) in 20% methanol/ethyl acetate (60 mL) is stirred at room temperaturefor 16 hours. The mixture is rotary evaporated. The residue ispartitioned between chloroform and 3% aqueous sodium carbonate. Theorganic layer is dried (magnesium sulfate) and rotary evaporated. Theresidue is purified by flash chromatography on silica gel (30% ethylacetate/hexane) to afford2-(t-butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole.

5-Amino-2-(t-butoxycarbonyl)amino-4,6-dimethylbenzimidazole. Asuspension of2-(t-butoxycarbonyl)amino-4,6-dimethyl-5-nitrobenzimidazole (0.625 g,2.04 mmol) in ethanol (70 mL) is treated with hydrogen at 45 psi for 15hours. The mixture is filtered on Celite and the filtrate is rotaryevaporated to afford5-amino-2-(t-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.5 g).

2-Amino-4,6-dimethyl-5-(2-imidazolinvlamino)benzimidazole. A mixture of5-amino-2-(t-butoxycarbonyl)amino-4,6-dimethylbenzimidazole (0.4 g, 1.44mmol), di-2-pyridyl thionocarbonate (1.0 g, 4.32 mmol) anddimethylaminopyridine (0.1 g) in methylene chloride (40 mL) and methanol(2 mL) is stirred at room temperature for 15 hours. This mixture is thenslowly added to a solution of 1,2-ethylene diamine (0.6 mL, 8.97 mmol)in methylene chloride (10 mL). The resulting mixture is stirred at roomtemperature for 1 hour. The mixture is rotary evaporated and the residueis triturated with ethyl acetate and filtered. The solid is suspended inmethanol (300 mL), mercuric acetate is added (0.56 g, 1.75 mmol) and theresulting mixture is stirred at room temperature for 15 hours. Themixture is filtered through Celite and the filtrate is rotaryevaporated. The residue is purified by preparative HPLC (C4 column,solvent gradient: 0.1% trifluoroacetic acid (in water)/acetonitrilestarting at 95/5 and going to 0/100) to afford2-amino-4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole as atrifluoroacetic acid salt.

Example 12

2-Amino-6-bromo-5-(2-imidazolinylamino)-4-methylbenzimidazole

This compound is prepared by a combination of Schemes 1 and 4.Commercially available 2,6-dinitrotoluene is converted to2,3-diamino-6-nitrotoluene according to scheme 2. Reaction with cyanogenbromide affords 2-amino-4-methyl-5-nitrobenzimidazole. After protectionof the amino group with a tert-butoxycarbonyl group, the compound isreduced by hydrogenation (palladium-on-carbon) and brominated (bromine,sodium acetate, acetic acid) to afford5-amino-6-bromo-2-tert-butoxycarbonylamino-4-methylbenzimidazole. Theformation of the 5-(2-imidazolinylamino) group is completed in the usualfashion and the tert-butoxycarbonyl group is cleaved by treatment withhydrobromic acid to afford2-amino-6-bromo-5-(2-imidazolinylamino)-4-methylbenzimidazole.

Example 13

2-Cyano-4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole

2-Amino-4,6-dimethyl-5-nitrobenzimidazole (as prepared in Example 11) isconverted to 2-cyano-4,6-dimethyl-5-nitrobenzimidazole by treatment withsodium nitrite and tetrafluoroboric acid followed by reaction withcopper cyanide. The synthesis of2-cyano-4,6-dimethyl-5-(2-imidazolinylamino)benzimidazole is thencompleted according to Scheme 5.

Example 14

6-Bromo-2-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole2-Amino-4-methyl-5-nitrobenzimidazole (see Example 12) is converted to2-cyano-4-methyl-5-nitrobenzimidazole by first treating with sodiumnitrate and tetrafluoroboric acid to form the diazonium salt, followedby reaction with copper cyanide. Reduction of the 5-nitro group followedby bromination (bromine, acetic acid) affords5-amino-6-bromo-2-cyano-4-methylbenzimidazole. The synthesis is thencompleted according to Scheme 5.

Example 15

2-Fluoro-7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole

3-Amino-2,6-dinitro-p-toluic carboxamide is converted to7-carboxamido-2-diazo-4-methyl-5-nitrobenzimidazole tetrafluoroborateaccording to Scheme 4. Conversion to7-carboxamido-2-fluoro-4-methyl-5-nitrobenzimidazole is achieved bythermal decomposition of the diazonium salt. The synthesis is thencompleted the same manner as in Example 1.

Example 16

4-Ethyl-2-fluoro-5-(2-imidazolinylamino)benzimidazole

2,4-Dinitro-3-ethyl-6-methylaniline (see Example 2) is treated withsodium sulfide to afford 1,2-diamino-3-ethyl-6-methyl-4-nitrobenzene.Treatment with cyanogen bromide affords to2-amino-4-ethyl-7-methyl-5-nitrobenzimidazole. This is converted to2-diazo-4-ethyl-7-methyl-5-nitrobenzimidazole tetrafuoroborate withsodium nitrite and tetrafluoroboric acid. Thermal decomposition of thediazonium salt gives 4-ethyl-2-fluoro-7-methyl-5-nitrobenzimidazole.Conversion to 4-ethyl-2-fluoro-5-(2-imidazolinylamino)benzimidazole iscompleted according to Scheme 5.

Examples 17-39

Compounds of formula

wherein R1, R2, R3, R4, and R5 are specified in the following table.Compounds of Example 17-39 are made using the methods explained andexemplified above.

Example R1 R2 R3 R4 R5 17 methyl H cyano H bromo 18 methyl H cyano Hchloro 19 methyl H cyano H hydroxy 20 methyl H hydroxy H H 21 methyl Hhydroxy methyl H 22 methyl H hydroxy H methyl 23 methyl H hydroxy Hfluoro 24 methyl H hydroxy H bromo 25 methyl H hydroxy h chloro 26methyl bromo H H fluoro 27 methyl bromo H H bromo 28 methyl bromo H Hhydroxy 29 methyl bromo H methyl H 30 methyl chloro H H H 31 methylchloro H methyl H 32 methyl chloro H H amino 33 methyl chloro H H fluoro34 methyl chloro H H bromo 35 methyl chloro H H methyl 36 methyl methylH methyl H 37 methyl methyl H H hydroxy 38 methyl methyl H H fluoro 39methyl methyl H H bromo 40 methyl methyl methyl H H 41 methyl bromomethyl H H 42 ethyl H bromo H H 43 ethyl H chloro H H 44 ethyl H hydroxyH H 45 ethyl H chloro methyl H 46 cyclopropyl H bromo H H 47 cyclopropylH chloro H H 48 cyclopropyl H hydroxy H H 49 cyclopropyl H methyl methylH

Compositions

Another aspect of this invention is compositions which comprise a safeand effective amount of a compound of the invention, or apharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable carrier. As used herein, “safe and effectiveamount” means an amount of the compound of the invention sufficient tosignificantly induce a positive modification in the condition to betreated, but low enough to avoid serious side effects (at a reasonablebenefit/risk ratio), within the scope of sound medical judgment. A safeand effective amount of the compound of the invention will vary with theage and physical condition of the patient being treated, the severity ofthe condition, the duration of the treatment, the nature of concurrenttherapy, the particular pharmaceutically-acceptable carrier utilized,and like factors within the knowledge and expertise of the attendingphysician.

Compositions of this invention preferably comprise from about 0.0001% toabout 99% by weight of the compound of the invention, more preferablyfrom about 0.01% to about 90%; also preferably from about 10% to about50%, also preferably from about 5% to about 10%, also preferably fromabout 1% to about 5%, and also preferably from about 0.1% to about 1%.

In addition to the compound of the invention, the compositions of thisinvention contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to a human or lower animal. Theterm “compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the compound of theinvention, and with each other, in a manner such that there is nointeraction which would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the human or lower animal being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens®; wetting agents, such as sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents; stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the compound of the invention is basically determinedby the way the compound is to be administered.

If the compound of the invention is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

The preferred mode of administering the compound of the invention isperorally. The preferred unit dosage form is therefore tablets,capsules, lozenges, chewable tablets, and the like. Such unit dosageforms comprise a safe and effective amount of the compound of theinvention, which is preferably from about 0.01 mg to about 200 mg, morepreferably from about 0.1 mg to about 50 mg, more preferably still fromabout 0.5 mg to about 25 mg, also preferably from about 1 mg to about 10mg. The pharmaceutically-acceptable carrier suitable for the preparationof unit dosage forms for peroral administration are well-known in theart. Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.001% toabout 5% of the compound of the invention, more preferably from about0.01% to about 0.5%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, Avicel® R C-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.Peroral liquid compositions may also contain one or more components suchas sweeteners, flavoring agents and colorants disclosed above.

Other modes of administration useful for attaining systemic delivery ofthe compounds of the invention include subcutaneous, intravenous,sublingual and buccal dosage forms. Such compositions typically compriseone or more of soluble filler substances such as sucrose, sorbitol andmannitol; and binders such as acacia, microcrystalline cellulose,carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants,lubricants, sweeteners, colorants, antioxidants and flavoring agentsdisclosed above may also be included.

A preferred mode of administering the compound of the invention istopically to the site where activity is desired: intranasal doses fornasal decongestion, inhalants for asthma, eye drops, gels and creams forocular disorders.

Preferred intranasal compositions of this invention include aqueoussolutions comprising a safe and effective amount of a compound of theinvention. Such compositions preferably comprise from about 0.001% toabout 5% of a compound of the invention, more preferably from about0.01% to about 0.5%. Such compositions also typically include safe andeffective amounts of preservatives, such as benzalkonium chloride andthimerosal; buffers such as phosphate and acetate; tonicity agents suchas sodium chloride; antioxidants such as ascorbic acid; aromatic agents;and acids and bases to adjust the pH of these aqueous compositions asneeded.

Preferred inhalation/atomization compositions of this invention includeaqueous solutions, suspensions, and dry powders comprising a safe andeffective amount of a compound of the invention. Such compositionspreferably comprise from about 0.1% to about 50% of a compound of theinvention, more preferably from about 1% to about 20%. Such compositionsare typically contained in a container with attached atomizing means.Such compositions also typically include propellants such aschlorofluorocarbons 12/11 and 12/114; solvents such as water, glyceroland ethanol; stabilizers such as ascorbic acid, sodium metabisulfite;preservatives such as cetylpyridinium chloride and benzalkoniumchloride; tonicity adjustors such as sodium chloride; and flavoringagents such as sodium saccharin.

Preferred intraocular compositions of this invention include aqueoussolutions comprising a safe and effective amount of a compound of theinvention. Such compositions preferably comprise from about 0.0001% toabout 5% of a compound of the invention, more preferably from about0.01% to about 0.5%. Such compositions also typically include one ormore of preservatives, such as benzalkonium chloride, thimerosal,phenylmercuric acetate; vehicles, such as poloxamers, modifiedcelluloses, povidone and purified water; tonicity adjustors, such assodium chloride, mannitol and glycerin; buffers such as acetate,citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases may be used to adjust the pH of these formulations as needed.

Additional Drug Actives

Compositions of this invention may optionally include other drugactives. Non-limiting examples of drug actives which may be incorporatedin these compositions include:

Antihistamines: Hydroxyzine preferably at a dosage range of from about25 to about 400 mg; Doxylamine, preferably at a dosage range of fromabout 3 to about 75 mg; Pyrilamine, preferably at a dosage range of fromabout 6.25 to about 200 mg; Chlorpheniramine, preferably at a dosagerange of from about 1 to about 24 mg; Phenindamine, preferably at adosage range of from about 6.25 to about 150 mg; Dexchlorpheniramine,preferably at a dosage range of from about 0.5 to about 12 mg;Dexbrompheniramine, preferably at a dosage range of from about 0.5 toabout 12 mg; Clemastine, preferably at a dosage range of from about 1 toabout 9 mg; Diphenhydramine, preferably at a dosage range of from about6.25 to about 300 mg; Azelastine, preferably at a dosage range of fromabout 140 to about 1,680 ug (when dosed intranasally); 1 to about 8 mg(when dosed orally); Acrivastine, preferably at a dosage range of fromabout 1 to about 24 mg; Levocarbastine (which can be dosed as anintranasal or ocular medicament), preferably at a dosage range of fromabout 100 to about 800 ug; Mequitazine, preferably at a dosage range offrom about 5 to about 20 mg; Astemizole, preferably at a dosage range offrom about 5 to about 20 mg; Ebastine;Loratadine, preferably at a dosagerange of from about 5 to about 40 mg; Cetirizine, preferably at a dosagerange of from about 5 to about 20 mg; Terfenadine, preferably at adosage range of from about 30 to about 480 mg; Terfenadine metabolites;Promethazine, preferably at a dosage range of from about 6.25 to about50 mg; Dimenhydrinate, preferably at a dosage range of from about 12.5to about 400 mg; Meclizine, preferably at a dosage range of from about6.25 to about 50 mg; Tripelennamine, preferably at a dosage range offrom about 6.25 to about 300 mg; Carbinoxamine, preferably at a dosagerange of from about 0.5 to about 16 mg; Cyproheptadine, preferably at adosage range of from about 2 to about 20 mg; Azatadine, preferably at adosage range of from about 0.25 to about 2 mg; Brompheniramine,preferably at a dosage range of from about 1 to about 24 mg;Triprolidine, preferably at a dosage range of from about 0.25 to about10 mg; Cyclizine, preferably at a dosage range of from about 12.5 toabout 200 mg; Thonzylamine, preferably at a dosage range of from about12.5 to about 600 mg; Pheniramine, preferably at a dosage range of fromabout 3 to about 75 mg; Cyclizine, preferably at a dosage range of fromabout 12.5 to about 200 mg and others.

Antitussives: Codeine, preferably at a dosage range of from about 2.5 toabout 120 mg; Hydrocodone, preferably at a dosage range of from about2.5 to about 40 mg; Dextromethorphan, preferably at a dosage range offrom about 2.5 to about 120 mg; Noscapine, preferably at a dosage rangeof from about 3 to about 180 mg; Benzonatate, preferably at a dosagerange of from about 100 to about 600 mg; Diphenhydramine, preferably ata dosage range of from about 12.5 to about 150 mg; Chlophedianol,preferably at a dosage range of from about 12.5 to about 100 mg;Clobutinol, preferably at a dosage range of from about 20 to about 240mg; Fominoben, preferably at a dosage range of from about 80 to about480 mg; Glaucine; Pholcodine, preferably at a dosage range of from about1 to about 40 mg; Zipeprol, preferably at a dosage range of from about75 to about 300 mg; Hydromorphone, preferably at a dosage range of fromabout 0.5 to about 8 mg; Carbetapentane, preferably at a dosage range offrom about 15 to about 240 mg; Caramiphen, Levopropoxyphene, preferablyat a dosage range of from about 25 to about 200 mg and others.

Antiinflammatories, preferably Non-Steroidal Anti-inflammatories(NSAIDS): Ibuprofen, preferably at a dosage range of from about 50 toabout 3,200 mg; Naproxen, preferably at a dosage range of from about62.5 to about 1,500 mg; Sodium naproxen, preferably at a dosage range offrom about 110 to about 1,650 mg; Ketoprofen, preferably at a dosagerange of from about 25 to about 300 mg; Indoprofen, Indomethacin,preferably at a dosage range of from about 25 to about 200 mg; Sulindac,preferably at a dosage range of from about 75 to about 400 mg;Diflunisal, preferably at a dosage range of from about 125 to about1,500 mg; Ketorolac, preferably at a dosage range of from about 10 toabout 120 mg; Piroxicam, preferably at a dosage range of from about 10to about 40 mg; Aspirin, preferably at a dosage range of from about 80to about 4,000 mg; Meclofenamate, preferably at a dosage range of fromabout 25 to about 400 mg; Benzydamine, preferably at a dosage range offrom about 25 to about 200 mg; Carprofen, preferably at a dosage rangeof from about 75 to about 300 mg; Diclofenac, preferably at a dosagerange of from about 25 to about 200 mg; Etodolac, preferably at a dosagerange of from about 200 to about 1,200 mg; Fenbufen, preferably at adosage range of from about 300 to about 900 mg; Fenoprofen, preferablyat a dosage range of from about 200 to about 3,200 mg; Flurbiprofen,preferably at a dosage range of from about 50 to about 300 mg; Mefenamicacid, preferably at a dosage range of from about 250 to about 1,500 mg;Nabumetone, preferably at a dosage range of from about 250 to about2,000 mg; Phenylbutazone, preferably at a dosage range of from about 100to about 400 mg; Pirprofen, preferably at a dosage range of from about100 to about 800 mg; Tolmetin, preferably at a dosage range of fromabout 200 to about 1,800 mg and others.

Analgesics: Acetaminophen, preferably at a dosage range of from about 80to about 4,000 mg; and others including narcotic and non-narcoticanalgesics.

Expectorants/Mucolytics: Guaifenesin, preferably at a dosage range offrom about 50 to about 2,400 mg; N-Acetylcysteine, preferably at adosage range of from about 100 to about 600 mg; Ambroxol, preferably ata dosage range of from about 15 to about 120 mg; Bromhexine, preferablyat a dosage range of from about 4 to about 64 mg; Terpin hydrate,preferably at a dosage range of from about 100 to about 1,200 mg;Potassium iodide, preferably at a dosage range of from about 50 to about250 mg and others.

Atropinics, preferably intranasally or orally administered atropinics:Ipratroprium (preferably intranasally), preferably at a dosage range offrom about 42 to about 252 ug; Atropine sulfate (preferably oral),preferably at a dosage range of from about 10 to about 1,000 ug;Belladonna (preferably as an extract), preferably at a dosage range offrom about 15 to about 45 mg equivalents; Scopolamine, preferably at adosage range of from about 400 to about 3,200 ug; Scopolaminemethobromide, preferably at a dosage range of from about 2.5 to about 20mg; Homatropine methobromide, preferably at a dosage range of from about2.5 to about 40 mg; Hyoscyamine (preferably oral), preferably at adosage range of from about 125 to about 1,000 ug; Isopropramide(preferably oral), preferably at a dosage range of from about 5 to about20 mg; Orphenadrine (preferably oral), preferably at a dosage range offrom about 50 to about 400 mg; Benzalkonium chloride (preferablyintranasally) preferably a 0.005 to about 0.1% solution and others.

Mast Cell Stabilizers, preferably intranasally, or orally administeredmast cell stabilizers: Cromalyn, preferably at a dosage range of fromabout 10 to about 60 mg; Nedocromil, preferably at a dosage range offrom about 10 to about 60 mg; Oxatamide, preferably at a dosage range offrom about 15 to about 120 mg; Ketotifen, preferably at a dosage rangeof from about 1 to about 4 mg; Lodoxamide, preferably at a dosage rangeof from about 100 to about 3,000 ug and others.

LT Antagonists: Zileuton and others.

Methylxanthines: Caffeine, preferably at a dosage range of from aboutabout 65 to about 600 mg; Theophyllene, preferably at a dosage range offrom about 25 to about 1,200 mg; Enprofylline; Pentoxifylline,preferably at a dosage range of from about 400 to about 3,600 mg;Aminophylline, preferably at a dosage range of from about 50 to about800 mg; Dyphylline, preferably at a dosage range of from about 200 toabout 1,600 mg and others.

Antioxidants or radical inhibitors: Ascorbic acid, preferably at adosage range of from about 50 to about 10,000 mg; Tocopherol, preferablyat a dosage range of from about 50 to about 2,000 mg; Ethanol,preferably at a dosage range of from about 500 to about 10,000 mg andothers.

Steroids, preferably intranasally administered steroids: Beclomethasone,preferably at a dosage range of from about 84 to about 336 ug;Fluticasone, preferably at a dosage range of from about 50 to about 400ug;

Budesonide, preferably at a dosage range of from about 64 to about 256ug;

Mometasone; Triamcinolone, preferably at a dosage range of from about110 to about 440 ug; Dexamethasone, preferably at a dosage range of fromabout 168 to about 1,008 ug; Flunisolide, preferably at a dosage rangeof from about 50 to about 300 ug; Prednisone (preferably oral),preferably at a dosage range of from about 5 to about 60 mg;Hydrocortisone (preferably oral), preferably at a dosage range of fromabout 20 to about 300 mg and others.

Bronchodilators, preferably for inhalation: Albuterol, preferably at adosage range of from about 90 to about 1,080 ug; 2 to about 76 mg (ifdosed orally); Epinephrine, preferably at a dosage range of from about220 to about 1,320 ug; Ephedrine, preferably at a dosage range of fromabout 15 to about 240 mg (if dosed orally); 250 to about 1,000 ug (ifdosed intranasally); Metaproterenol, preferably at a dosage range offrom about 65 to about 780 ug or 10 to about 80 mg if dosed orally;Terbutaline, preferably at a dosage range of from about 200 to about2,400 ug; 2.5 to about 20 mg if dosed orally; Isoetharine, preferably ata dosage range of from about 340 to about 1,360 ug; Pirbuterol,preferably at a dosage range of from about 200 to about 2,400 ug;Bitolterol, preferably at a dosage range of from about 370 to about2,220 ug; Fenoterol, preferably at a dosage range of from about 100 toabout 1,200 ug; 2.5 to about 20 mg (if dosed orally); Rimeterol,preferably at a dosage range of from about 200 to about 1,600 ug;Ipratroprium, preferably at a dosage range of from about 18 to about 216ug (inhalation) and others.

Antivirals: Amantadine, preferably at a dosage range of from about 50 toabout 200 mg; Rimantadine, preferably at a dosage range of from about 50to about 200 mg; Enviroxime; Nonoxinols, preferably at a dosage range offrom about 2 to about 20 mg (preferably an intranasal form); Acyclovir,preferably at a dosage range of from about 200 to about 2,000 mg (oral);1 to about 10 mg (preferably an intranasal form); Alpha-interferon,preferably at a dosage range of from about 3 to about 36 MIU;Beta-Interferon, preferably at a dosage range of from about 3 to about36 MIU and others.

Ocular Drug actives: acetylcholinesterase inhibitors, e.g.,echothiophate from about 0.03% to about 0.25% in topical solution andothers; and

Gastrointestinal actives: antidiarrheals, e.g., loperamide from about0.1 mg to about 1.0 mg per dose, and bismuth subsalicylate from about 25mg to about 300 mg per dose and others.

An active may be useful for more than one of the above uses, and theseuses are clearly contemplated as well. This overlap is recognized in theart and adjusting dosages and the like to fit the indication is wellwithin the ability of the skilled medical practitioner.

Methods of use

The compounds of the present invention are useful in treating manymedical disorders, including for example, respiratory disorders, oculardisorders, gastrointestinal disorders, disorders associated withsympathetic nervous system activity, migraine, peripheral pain, anddisorders where vasoconstriction would provide a benefit.

The preferred routes of administration are peroral; intranasal;parenteral; subcutaneous; and topical.

Another aspect of the invention involves methods for preventing ortreating nasal congestion by administering a safe and effective amountof a subject compound to a human or lower animal experiencing or at riskof experiencing nasal congestion. Such nasal congestion may beassociated with human diseases or disorders which include, but are notlimited to, seasonal allergic rhinitis, acute upper respiratory viralinfections, sinusitis, perennial rhinitis, and vasomotor rhinitis. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.001 mg/kg to about 10 mg/kg of acompound, more preferably from about 0.01 mg/kg to about 5 mg/kg, morepreferably still from about 0.1 mg/kg to about 1 mg/kg. Peroral orintranasal administration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily. Such doses and frequenciesare also preferred for treating other respiratory conditions, such asotitis media, cough, COPD and asthma.

Another aspect of this invention involves methods for preventing ortreating glaucoma by administering a safe and effective amount of asubject compound to a mammal experiencing or at risk of experiencingglaucoma. If administered systemically, each administration of a dose ofthe subject compound preferably administers a dose within the range offrom about 0.0001 mg/kg to about 5 mg/kg of a compound, more preferablyfrom about 0.001 mg/kg to about 0.5 mg/kg. If intraocular dosing is usedthen preferably one administers a typical volume (for example, 1 or 2drops) of a liquid composition, comprising from about 0.0001% to about5% of a subject compound, more preferably from about 0.01% to about 0.5%of the compound. Determination of the exact dosage and regimen is withinthe purview of the skilled artisan. Intraocular administration of suchdoses is preferred. The frequency of administration of a subjectcompound according to this invention is preferably from about once toabout six times daily, more preferably from about once to about 4 timesdaily.

Another aspect of this invention involves methods for preventing ortreating migraine, by administering a safe and effective amount of asubject compound to a human or lower animal experiencing or at risk ofexperiencing migraine. Each administration of a dose of the subjectcompound preferably administers a dose within the range of from about0.001 mg/kg to about 10 mg/kg of a compound, more preferably from about0.01 mg/kg to about 5 mg/kg, more preferably still from about 0.1 mg/kgto about 1 mg/kg. Peroral or intranasal administration of such doses ispreferred. The frequency of administration of a subject compoundaccording to this invention is preferably from about once to about sixtimes daily, more preferably from about 2 times to about 4 times daily.

Another aspect of this invention involves methods for preventing ortreating functional bowel disorders, such as diarrhea, by administeringa safe and effective amount of a subject compound to a human or loweranimal experiencing or at risk of experiencing diarrhea. Eachadministration of a dose of the subject compound preferably administersa dose within the range of from about 0.001 mg/kg to about 10 mg/kg of acompound, more preferably from about 0.01 mg/kg to about 5 mg/kg, morepreferably still from about 0.1 mg/kg to about 1 mg/kg. Peroraladministration of such doses is preferred. The frequency ofadministration of a subject compound according to this invention ispreferably from about once to about six times daily, more preferablyfrom about 2 times to about 4 times daily.

Dosages may be varied based on the patient being treated, the conditionbeing treated, the severity of the condition being treated, the route ofadministration, etc. to achieve the desired effect.

Composition and Method Examples

The following non-limiting examples illustrate the subject invention.The following composition and method examples do not limit theinvention, but provide guidance to the skilled artisan to prepare anduse the compounds, compositions and methods of the invention. In eachcase other compounds within the invention may be substituted for theexample compound shown below with similar results. The skilledpractitioner will appreciate that the examples provide guidance and maybe varied based on the condition being treated and the patient.

Example A

Oral Tablet Composition Ingredient Amount per tablet (mg) Compound ofExample 1 20.0 Microcrystaliine cellulose (Avicel PH 102 ®) 80.0Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil ®) 1.0 Magnesiumstearate 3.0 Total = 200.0

One tablet is swallowed by a patient with nasal congestion. Thecongestion is substantially diminished.

Example B

Chewable Tablet Composition Ingredient Amount per tablet (mg) Compoundof Example 2 15.0 Mannitol 255.6 Microcrystaliine cellulose (Avicel PH101 ®) 100.8 Dextrinized sucrose (Di-Pac ®) 199.5 Imitation orangeflavor 4.2 Sodium saccharin 1.2 Stearic acid 15.0 Magnesium stearate 3.0FD&C Yellow #6 dye 3.0 Pyrogenic silica (Cab-O-Sil ®) 2.7 Total = 600.0

One tablet is chewed and swallowed by a patient with nasal congestion.The congestion is substantially reduced.

Example C

Sublingual Tablet Composition Ingredient Amount per tablet (mg) Compoundof Example 3 2.00 Mannitol 2.00 Microcrystalline cellulose (Avicel PH101 ®) 29.00 Mint flavorants 0.25 Sodium saccharin 0.08 Total = 33.33

One tablet is placed under the tongue of a patient with nasal congestionand allowed to dissolve. The congestion is rapidly and substantiallydiminished.

Example D

Intranasal Solution Composition Ingredient Composition (% w/v) Compoundof Example 4 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002 d-Sorbitol5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total = 100.00

One-tenth of a mL of the composition is sprayed from a pump actuatorinto each nostril of a patient with nasal congestion. The congestion issubstantially diminished.

Example E

Intranasal Gel Composition Ingredient Composition (% w/v) Compound ofExample 5 0.10 Benzalkonium chloride 0.02 Thimerosal 0.002 Hydroxypropylmethylcellulose 1.00 (Metolose 65SH4000 ®) Aromatics 0.06 Sodiumchloride (0.65%) q.s. Total = 100.00

One-fifth of a mL of the composition is applied as drops from a dropperinto each nostril of a patient with nasal congestion. The congestion issubstantially reduced.

Example F

Inhalation Aerosol Composition Ingredient Composition (% w/v) Compoundof Example 1 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 SodiumSaccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0

Two-puffs of the aerosol composition is inhaled from a metered-doseinhaler by a patient with asthma. The asthmatic condition is effectivelyrelieved.

Example G

Topical Ophthalmic Composition Ingredient Composition (% w/v) Compoundof Example 7 0.10 Benzalkonium chloride 0.01 EDTA 0.05Hydroxyethylcellulose (Natrosol M ®) 0.50 Sodium metabisulfite 0.10Sodium chloride (0.9%) q.s. Total = 100.0

One-tenth of a mL of the composition is administered directly into eacheye of a patient with glaucoma. The intraocular pressure issubstantially reduced.

Example H

Oral Liquid Composition Ingredient Amount/15 mL Dose Compound of Example1 15 mg Chlorpheniramine maleate 4 mg Propylene glycol 1.8 g Ethanol(95%) 1.5 mL Methanol 12.5 mg Eucalyptus oil 7.55 mg Flavorants 0.05 mLSucrose 7.65 g Carboxymethylcellulose (CMC) 7.5 mg Microcrystallinecellulose and 187.5 mg Sodium CMC (Avicel RC 591 ®) Polysorbate 80 3.0mg Glycerin 300 mg Sorbitol 300 mg FD&C Red #40 dye 3 mg Sodiumsaccharin 22.5 mg Sodium phosphate monobasic 44 mg Sodium citratemonohydrate 28 mg Purified Water q.s. Total = 15 mL

One 15 mL dose of the liquid composition is swallowed by a patient withnasal congestion, runny nose and sneezing due to allergic rhinitis. Thecongestion, runny nose and sneezing are effectively reduced.

Example J

Oral Liquid Composition Ingredient Amount/15 mL Dose Compound of Example7 30 mg Sucrose 8.16 g Glycerin 300 mg Sorbitol 300 mg Methylparaben19.5 mg Propylparaben 4.5 mg Menthol 22.5 mg Eucalyptus oil 7.5 mgFlavorants 0.07 mL FD&C Red #40 dye 3.0 mg Sodium saccharin 30 mgPurified water q.s. Total = 15 mL

One 15 mL dose of the alcohol-free liquid medication is swallowed by apatient with nasal congestion. The congestion is substantiallydiminished.

Example K

Oral Tablet composition Ingredient Amount per tablet (mg)Chlorpheniramine maleate, USP 4.0 Compound of Example 8 4.0Microcrystalline cellulose, NF 130.0 Starch 1500, NF 100.0 Magnesiumstearate, USP 2.0 Total = 240.0

For the relief of nasal congestion due to the common cold, hay fever, orother upper respiratory allergies, or associated with sinusitis;relieves runny nose, sneezing, and itchy watery eyes as may occur inallergic rhinitis. Restores freer breathing through the nose. Adults 12and over take one tablet every four hours.

Example L

Oral Tablet Composition Ingredient Amount per tablet (mg) Loratadine 5.0Compound of Example 9 12.0 Hydroxypropyl methylcellulose, USP 12.0Magnesium stearate, USP 2.0 Lactose anhydrous, USP 200.0 Total = 231.0

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, and nasal congestion. Adults 12 and over take onetablet every twelve hours.

Example M

Oral Caplet Composition Ingredient Amount per caplet (mg) Naproxensodium anhydrous, USP 220.0 Compound of Example 10 6.0 Hydroxypropylmethylcellulose, USP 6.0 Magnesium stearate, USP 2.0 Povidone K-30, USP10.0 Talc, USP 12.0 Microcrystalline cellulose, NF 44.0 Total = 300.0

For relief of symptoms associated with the common cold, sinusitis, orflu including nasal congestion, headache, fever, body aches, and pains.Adults 12 and over take two caplets every twelve hours.

Example N

Oral Tablet Composition Ingredient mg/tablet Acetaminophen, USP 500.0Compound of Example 1 6.0 Hydroxypropyl methylcellulose, USP 6.0 Silicondioxide, colloidal, NF 30.0 Pregelatinized starch, NF 50.0 Magnesiumstearate, USP 4.0 Total = 596.0

For relief of nasal/sinus congestion and pressure, sinus headache painassociated with sinusitis, hay fever, upper respiratory allergies, orthe common cold. Adults 12 and over take one tablet every six hours.

Example O

Oral Caplet Composition Ingredient Amount per caplet (mg) Naproxensodium anhydrous, USP 220.0 Loratadine 2.5 Compound of Example 3 6.0Hydroxypropyl methylcellulose, USP 6.0 Magnesium stearate, USP 2.0Povidone K-30, USP 10.5 Talc, USP 12.0 Microcystalline cellulose, NF44.0 Total = 303.0

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, nasal congestion, sinus pain, and headache. Adults12 and over take two caplets every twelve hours.

Example P

Oral Tablet Composition Ingredient Amount per tablet (mg) Naproxensodium anhydrous, USP 220.0 Chlorpheniramine maleate, USP 6.0 Compoundof Example 2 6.0 Hydroxypropyl methylcellulose, USP 12.0 Magnesiumstearate, USP 2.0 Povidone K-30, USP 10.0 Talc, USP 12.0Microcrystalline cellulose, NF 44.0 Total = 312.0

For the relief of symptoms due to the common cold, flu, hay fever, orother upper respiratory allergies, or associated with sinusitis;relieves runny nose, sneezing, and itchy watery eyes as may occur inallergic rhinitis. Relieves headache, fever, body aches, and pains.Restores freer breathing through the nose. Adults 12 and over take twotablets every twelve hours.

Example Q

Oral Tablet Composition Ingredient Amount per tablet (mg) Acetaminophen,USP 500.0 Loratadine 1.3 Compound of Example 4 3.0 Hydroxypropylmethylcellulose, USP 3.0 Silicon dioxide, colloidal, NF 30.0Pregelatinized starch, NF 50.0 Magnesium stearate, USP 2.7 Total = 590.0

For the relief of symptoms associated with allergic rhinitis such assneezing, rhinorrhea, nasal congestion, sinus pain, and headache. Adults12 and over take two tablets every six hours.

Example R

Oral Tablet Composition Ingredient Amount per tablet (mg) Compound ofExample 1 20.0 Microcrystalline cellulose (Avicel PH 102 ®) 80.0Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil ®) 1.0 Magnesiumstearate 3.0 Total = 200.0

One tablet is swallowed by a patient with migraine. The pain and aura ofmigraine is substantially diminished.

Example S

Oral Tablet Composition Ingredient Amount per tablet (mg) Compound ofExample 1 20.0 Microcrystalline cellulose (Avicel PH 102 ®) 80.0Dicalcium phosphate 96.0 Pyrogenic silica (Cab-O-Sil ®) 1.0 Magnesiumstearate 3.0 Total = 200.0

One tablet is swallowed by a patient with diarrhea. The diarrhea issubstantially diminished.

Other examples of combination actives are contemplated. Examples ofmedicaments which can be combined with the primary active are includedin U.S. Pat. No. 4,552,899 to Sunshine, et al., hereby incorporated byreference. All other references referred to throughout thisspecification are hereby incorporated by reference.

While particular embodiments of this invention have been described, itwill be obvious to those skilled in the art that various changes andmodifications of this invention can be made without departing from thespirit and scope of the invention. It is intended to cover, in theappended claims, all such modifications that are within the scope ofthis invention.

What is claimed is:
 1. A compound having the following structure:

wherein: (a) R1 is alkyl; (b) R2 is selected from the group consistingof: hydrogen, alkyl, methoxy, cyano, and halo; (c) R3 is selected formthe group consisting of: hydrogen, methyl, hydroxy, cyano and halo; (d)R4 is hydrogen; (e) R5 is selected from the group consisting of:hydrogen, methyl, amino, methoxy, hydroxy, cyano and halo; (f) providedthat at least one of R2, R3, or R5 is other than hydrogen or fluorine;(g) provided that when R1 is methyl and both R2 and R5 are hydrogen, R3is other than methyl or halo; (h) provided that when R3 is cyano, R1 ismethyl; and any tautomer of the above structure or pharmaceuticallyacceptable salt, or biohydrolyzable ester, amide, or imide thereof. 2.The compound according to claim 1 characterized in that R2 and R5 areindependently selected from the group consisting of: hydrogen, methyl,and halo.
 3. The compound according to claim 1 or 2 characterized inthat R1 is methyl and R3 is cyano or hydroxy.
 4. The compound accordingto claim 1 or 2 characterized in that R1 is ethyl or cyclopropyl and R3is selected from the group consisting of: methyl, hydroxy, and halo. 5.The compound according to claim 1 characterized in that the compound isselected from the group consisting of:7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole,7-hydroxy-5-(2-imidazolinylamino)-4-methylbenzimidazole,4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole, and4-cyclopropyl-5-(2-imidazolinylamino)-7-methylbenzimidazole.
 6. Apharmaceutical composition comprising: (a) a safe and effective amountof a compound of claim 1, and (b) a pharmaceutically-acceptable carrier.7. A method of preventing or treating alpha-2 mediated disorders byadministering to a human or lower animal in need of such treatment, asafe and effective amount of a compound of claim
 1. 8. The method ofclaim 7 wherein the disorder is selected form the group consisting of:respiratory disorder, ocular disorder, gastrointestinal disorder, adisorder associated with sympathetic nervous system activity, migraine,peripheral pain, and a disorder where vasoconstriction would provide abenefit.
 9. The method of claim 8 wherein the disorder is nasalcongestion.
 10. The method of claim 8 wherein the disorder is glaucoma.11. The method of claim 8 wherein the disorder is asthma.
 12. The methodof claim 8 wherein the disorder is migraine.
 13. The method of claim 8wherein the disorder is diarrhea.
 14. A pharmaceutical compositioncomprising the compound of claim 1 and one or more actives chosen fromthe group consisting of an antihistamine, antitussive, mast cellstabilizer, LT antagonist, expectorant/mucolytic, antioxidant or radicalinhibitor, steroid, bronchodilator, antiviral, analgesic,anti-inflammatory, gastrointestinal, and ocular active.
 15. Thepharmaceutical composition of claim 6 wherein R1 is methyl, R2 ishydrogen, R3 is cyano, R4 is hydrogen, and R5 is hydrogen.
 16. Thepharmaceutical composition of claim 14 wherein R1 is methyl, R2 ishydrogen, R3 is cyano, R4 is hydrogen, and R5 is hydrogen.
 17. Themethod of claim 7 wherein R1 is methyl, R2 is hydrogen, R3 is cyano, R4is hydrogen, and R5 is hydrogen.
 18. The method of claim 8 wherein R1 ismethyl, R2 is hydrogen, R3 is cyano, R4 is hydrogen, and R5 is hydrogen.19. The method of claim 8 wherein the disorder is peripheral pain.